ABSTRACT
BACKGROUND
Elective freezing of all good quality embryos and transfer in subsequent cycles, i.e. elective frozen embryo transfer (eFET), has recently increased significantly with the ...introduction of the GnRH agonist trigger protocol and improvements in cryo-techniques. The ongoing discussion focuses on whether eFET should be offered to the overall IVF population or only to specific subsets of patients. Until recently, the clinical usage of eFET was supported by only a few randomized controlled trials (RCT) and meta-analyses, suggesting that the eFET not only reduced ovarian hyperstimulation syndrome (OHSS), but also improved reproductive outcomes. However, the evidence is not unequivocal, and recent RCTs challenge the use of eFET for the general IVF population.
OBJECTIVE AND RATIONALE
This systematic review and meta-analysis aimed at evaluating whether eFET is advantageous for reproductive, obstetric and perinatal outcomes compared with fresh embryo transfer in IVF/ICSI cycles. Additionally, we evaluated the effectiveness of eFET in comparison to fresh embryo transfer in different subgroups of patients undergoing IVF/ICSI cycles.
SEARCH METHODS
We conducted a systematic review, using PubMed/Medline and EMBASE to identify all relevant RCTs published until March 2018. The participants included infertile couples undergoing IVF/ICSI with or without preimplantation genetic testing for aneuploidy (PGT-A). The primary outcome was the live birth rate (LBR), whereas secondary outcomes were cumulative LBR, implantation rate, miscarriage, OHSS, ectopic pregnancy, preterm birth, pregnancy-induced hypertension, pre-eclampsia, mean birthweight and congenital anomalies. Subgroup analyses included normal and hyper-responder patients, embryo developmental stage on the day of embryo transfer, freezing method and the route of progesterone administration for luteal phase support in eFET cycles.
OUTCOMES
Eleven studies, including 5379 patients, fulfilling the inclusion criteria were subjected to qualitative and quantitative analysis. A significant increase in LBR was noted with eFET compared with fresh embryo transfer in the overall IVF/ICSI population risk ratio (RR) = 1.12; 95% CI: 1.01–1.24. Subgroup analyses indicated higher LBRs by eFET than by fresh embryo transfer in hyper-responders (RR = 1.16; 95% CI: 1.05–1.28) and in PGT-A cycles (RR = 1.55; 95% CI: 1.14–2.10). However, no differences were observed for LBR in normo-responders (RR = 1.03; 95% CI: 0.91–1.17); moreover, the cumulative LBR was not significantly different in the overall population (RR = 1.04; 95% CI: 0.97–1.11). Regarding safety, the risk of moderate/severe OHSS was significantly lower with eFET than with fresh embryo transfer (RR = 0.42; 95% CI: 0.19–0.96). In contrast, the risk of pre-eclampsia increased with eFET (RR = 1.79; 95% CI: 1.03–3.09). No statistical differences were noted in the remaining secondary outcomes.
WIDER IMPLICATIONS
Although the use of eFET has steadily increased in recent years, a significant increase in LBR with eFET was solely noted in hyper-responders and in patients undergoing PGT-A. Concerning safety, eFET significantly decreases the risk of moderate and severe OHSS, albeit at the expense of an increased risk of pre-eclampsia.
Societal changes and the increasing desire and opportunity to preserve fertility have increased the demand for effective assisted reproductive technologies (ART) and have increased the range of ...scenarios in which ART is now used. In recent years, the "freeze-all" strategy of cryopreserving all oocytes or good quality embryos produced in an IVF cycle to transfer later-at a time that is more appropriate for reasons of medical need, efficacy, or desirability-has emerged as an accepted and valuable alternative to fresh embryo transfer. Indeed, improvements in cryopreservation techniques (vitrification) and the development of more efficient ovarian stimulation protocols have facilitated a dramatic increase in the practice of elective frozen embryo transfer (eFET). Alongside these advances, debate continues about whether eFET should be a standard treatment option available to the whole IVF population or if it is important to identify patient subgroups who are most likely to benefit from such an approach. Achieving successful outcomes in ART, whether by fresh or frozen embryo transfer, is influenced by a wide range of factors. As well as the efficiency of IVF and embryo transfer protocols and techniques, factors affecting implantation include maternal aging, sperm quality, the vaginal and endometrial microbiome, and peri-implantation levels of serum progesterone. The safety of eFET, both during ART cycles and on longer-term obstetric and neonatal outcomes, is also an important consideration. In this review, we explore the benefits and risks of freeze-all strategies in different scenarios. We review available evidence on the outcomes achieved with elective cryopreservation strategies and practices and how these compare with more traditional IVF cycles with fresh embryo transfers, both in the general IVF population and in subgroups of special interest. In addition, we consider how to optimize and individualize "freeze-all" procedures to achieve successful reproductive outcomes.
IntroductionThis study compares rectal administration with vaginal administration of progesterone as luteal phase support in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles. The ...reason for comparing the two routes of administration is that rectal administration has been suggested to be more patient friendly.Methods and analysisThis study is a randomised controlled trial comparing the ongoing pregnancy rate (OPR) at week 12 in HRT-FET cycles after rectal administered progesterone as the only administered progesterone compared with a vaginal luteal phase support regimen. All patients are enrolled from a Danish public fertility clinic and randomised to one of two groups, with 305 patients receiving embryo transfer assigned to each group. Endometrial preparation includes 6 mg oestradiol daily. The intervention group receives rectally administered progesterone (400 mg/12 hours) and the control group receives vaginally administered progesterone (400 mg/12 hours). If P4 is <35 nmol/L on blastocyst transfer day an additional rectal luteal phase rescue regimen is started (control group). Thawing and transferring of a single autologous vitrified blastocyst is scheduled on the sixth day of progesterone administration in both groups. The power calculation is based on a non-inferiority analysis with an expected OPR in both groups of 44% and the upper limit of a one-sided 95% CI will exclude a difference in favour of the control group of more than 10.0%. An interim analysis will be conducted once half of the study population has been enrolled.Ethics and disseminationThe trial was approved on 21 November 2023 by the Danish National Ethical Committee and the Danish Medicines Agency and is authorised by the Clinical Trials Information System (EUCT number 2023-504616-15-02). All patients will provide informed consent before being enrolled in the study. The results will be published in an international journal.Trial registration numberEUCT number: 2023-504616-15-02.
Abstract Gonadotrophin releasing hormone agonist (GnRHa) trigger is effective in the induction of oocyte maturation and prevention of ovarian hyperstimulation syndrome during IVF treatment. This ...trigger concept, however, results in early corpora lutea demise and consequently luteal phase dysfunction and impaired endometrial receptivity. The aim of this strenghths, weaknesses, opportunities and threats analysis was to summarize the progress made over the past 15 years to optimize ongoing pregnancy rates after GnRHa trigger. The advantages and potential drawbacks of this type of triggering are reviewed. The current approach to the management of GnRHa trigger in autologous cycles is based on the peak serum oestradiol level or follicle number and aims at a fresh embryo transfer or a segmentation approach with elective cryopreservation policy. We recommend intensive luteal support with transdermal oestradiol and intramuscular progesterone alone if peak serum oestradiol is 4000 or more pg/ml after GnRHa trigger or dual trigger with GnRHa and HCG 1000 IU if peak serum oestradiol is less than 4000 pg/mL. On the contrary, we recommend HCG 1500 IU 35 h after GnRHa trigger if there are less than 25 follicles, or freeze all oocytes or embryos if there are over 25 follicles.
Poor ovarian response (POR) to controlled ovarian stimulation (OS) presents a major challenge in assisted reproduction. The Bologna criteria represented the first serious attempt to set clear ...criteria for the definition of POR. However, the Bologna criteria were questioned because of the persistent heterogeneity among POR patients and the inability to provide management strategies. Based on these facts, a more recent classification, the POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) classification, was developed to provide a homogeneous and refined definition of POR that significantly reduces the heterogeneity of the Bologna criteria definition of POR and helps in the clinical handling and counseling of patients. In this review, we discuss the impact of the POSEIDON classification on the clinical management of patients with POR.
To reevaluate ovarian hyperstimulation syndrome (OHSS) prevention techniques and provide a classification system for grading OHSS and evidence-based treatment strategies for preventing OHSS.
A ...literature search was conducted in PubMed for articles published in the last 5 years using the keywords "controlled ovarian stimulation," "controlled ovarian hyperstimulation," "ovarian hyperstimulation syndrome," "OHSS," "prevention," "chorionic gonadotropin," "hCG," "GnRH agonist," "GnRH antagonist," "coasting," and "cryopreservation." We reviewed randomized controlled trials (RCTs), retrospective studies, pilot studies, case studies, reviews, and meta-analyses.
There is a shortage of large, prospective RCTs reporting OHSS prediction and prevention strategies. Our review showed that risk factors such as antral follicle count and baseline anti-Müllerian hormone level may identify women at high OHSS risk. Preventative strategies that appear highly effective at reducing or preventing OHSS include GnRH antagonist protocols and the use of GnRH agonists to trigger final oocyte maturation. Moreover, alternative therapies, such as dopamine receptor agonists (Cabergoline), have also emerged as potential new treatment modalities in the management of this disease.
These findings suggest that current treatment guidelines should be updated to incorporate findings from recent literature that show that GnRH antagonist protocols consistently reduce OHSS and that GnRH agonist triggering has considerable promise in preventing OHSS, although further RCTs will be needed to confirm this.
The challenges in attaining an adequate luteal phase after GnRH agonist (GnRHa) trigger to induce final oocyte maturation have resulted in different approaches focused on rescuing the luteal phase ...insufficiency so that a fresh transfer can be carried out without jeopardizing IVF outcomes. Over the years, two different concepts have emerged: intensive luteal support with aggressive exogenous administration of E2 and P; and low-dose hCG rescue in the form of a small dose of hCG either on the day of oocyte retrieva or on the day of GnRHa trigger (the so called "dual trigger"). Both approaches have been shown to be effective in achieving pregnancy rates similar to those obtained after conventional hCG trigger and resulting in a very low risk of ovarian hyperstimulation syndrome (OHSS). Although the idea of freezing all embryos after GnRHa trigger and transferring them in a subsequent frozen-thawed cycle has been gaining momentum, a fresh transfer leading to the live birth of a healthy child is currently considered to be the goal of IVF treatment.
Controlled ovarian stimulation with subsequent multi-follicular development continues to be a keystone in ART. Evidence supports an individualized approach to ovarian stimulation, usually involving ...combinations of ovarian reserve tests, body mass index and age to tailor the exogenous gonadotropin dose, and potentially adjuvant treatment aiming for high safety and a shortening of time to live birth. While stimulation and trigger concepts have been developed successfully in normo- and hyperresponder patients, the poor responder patient remains difficult to manage. However, recent advances in definition and classification of the expected poor ovarian responder patient might enable a more accurate and clinically useful interpretation of new treatment concepts in a more homogenous study population. In the present review, we discuss the classification of the expected poor ovarian responder patient as well as clinically useful measurements of efficacy for controlled ovarian stimulation, and finally, we discuss the evidence for clinical management of patients with expected poor ovarian response, including adjuvant treatments such as growth hormone, androgens, and LH activity.In conclusion, the best available evidence supports that the treatment of the expected poor ovarian response patient should be individualized in all steps of ART, including the choice of GnRH analogue, the gonadotropin type and dose, ovulation trigger, and the possible use of adjuvant therapies.
To investigate the possible effect of controlled ovarian stimulation on the perinatal outcomes of assisted reproductive technology pregnancies, by comparing the outcomes from fresh ET with frozen ET ...(FET) with blastocysts of similar quality.
Retrospective observational study.
Private fertility center.
Seven hundred eighty-four fresh transfers and 382 vitrified-warmed double blastocyst transfers.
None.
Miscarriage, perinatal mortality, preterm delivery, live birth, live-birth weights, and gestational age of live births.
FET resulted in higher implantation rates (51.5% vs. 40.6%), higher live-birth rates per transfer (56.8% vs. 44.3%), and lower ectopic pregnancy rates (0.32% vs. 1.80%). FET pregnancies also had higher day 14 βhCG levels per implantation (148.2 vs. 176.2 IU/L) and higher infant birth weights (singletons Δ109.4 g, twins Δ124 g). Female infants benefitted the most in terms of birth weight. Miscarriage, premature delivery, perinatal morbidity, and live birth per pregnancy were all nonsignificantly different between fresh ET and FET.
Clinically significant differences between the peri-implantation and perinatal outcomes of fresh ET and FET suggest better endometrial receptivity and placentation in FET cycles.
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